Medicinal inhalation devices and components thereof

ABSTRACT

A medicinal inhalation device having applied to surface thereof a composition comprising a monofunctional polyfluoropolyether silane and a non-fluorinated cross-linking agent.

FIELD OF THE INVENTION

The present invention relates to medicinal inhalation devices andcomponents for such devices as well as methods of making such devicesand components.

BACKGROUND OF THE INVENTION

Medicinal inhalation devices, including pressurized inhalers, such asmetered dose pressurized inhalers (MDIs), and dry powder inhalers(DPIs), are widely used for delivering medicaments.

Medicinal inhalation devices typically comprise a plurality of hardwarecomponents, (which in the case of a MDI can include gasket seals;metered dose valves (including their individual components, such asferrules, valve bodies, valve stems, tanks, springs retaining cups andseals); containers; and actuators) as well as a number of internalsurfaces which may be in contact with the medicinal formulation duringstorage or come in contact with the medicinal formulation duringdelivery. Often a desirable material for a particular component is foundto be unsuitable in regard to its surface properties, e.g. surfaceenergy, and/or its interaction with the medicinal formulation. Forexample, the relatively high surface energy of materials typically usedin MDIs, e.g. acetal polymer for valve stems, or deep drawn stainlesssteels or aluminum for containers, can cause medicament particles insuspension formulations to adhere irreversibly to the surfaces ofcorresponding component(s), which has a consequent impact on theuniformity of medicinal delivery. Similar effects are also observed forDPIs. Other examples of potentially undesirable interactions between acomponent and the medicinal formulation may include enhanced medicamentdegradation; adsorption of medicament or permeation of a formulationconstituent or extraction of chemicals from plastic materials. For DPIsoften permeation and adsorption of ambient water pose issues. Also theuse of materials having relatively high surface energy for certaincomponents (e.g. metered dose valves and/or individual componentsthereof), may have undesirable effects for the operation of movablecomponents of a medicinal inhalation device.

Various coatings have been proposed for particular components orsurfaces of metered dose inhalers, see e.g. EP 642 992, WO 96/32099, WO96/32150-1, WO 96/32345, WO 99/42154, WO 02/47829, WO03/024623; WO02/30498, WO 01/64273; WO 91/64274-5; WO 01/64524; and WO 03/006181.

SUMMARY OF THE INVENTION

Although a number of different coatings have been proposed, there is anongoing need for medicinal inhalation devices and components thereofhaving desirable surface properties (e.g. low surface energy) inconjunction with desirable structural integrity (e.g. adhesion,durability, robustness and/or resistance to degradation over thelifetime of the device) of a coating system provided on said devices andcomponents as well as methods of providing such medicinal inhalationdevices and components.

In aspects of the present invention there is provided a method of makinga medicinal inhalation device or a component of a medicinal inhalationdevice comprising a step of: applying to at least a portion of a surfaceof the device or the component, respectively, a composition comprising amonofunctional polyfluoropolyether silane and a non-fluorinatedcross-linking agent.

It has been found that the use of a monofunctional polyfluoropolyethersilane in conjunction with a non-fluorinated cross-linking agent allowsfor high application efficiency and coverage as well as extensivebonding (e.g. covalent bonding) to said surface as well as cross-linkingwithin the polyfluoropolyether-containing coating itself, to providevery desirable structural integrity of appliedpolyfluoropolyether-containing coating.

The term “monofunctional polyfluoropolyether silane” as used herein isgenerally understood to mean a monovalent polyfluoropolyether segmentfunctionalized with one or more functional silane groups (in particularone functional silane group or two functional silane groups).

For enhanced stability and/or resistance to attack (e.g. by ethanol,medicament, and/or other potential components of medicinal inhalationformulations) desirably the polyfluoropolyether segment is not linked tosilane group(s) via a functionality that includes a nitrogen-siliconbond or a sulfur-silicon bond. In particular, for enhanced stability andresistance of the applied polyfluoropolyether-containing coating toattack, it is desirable that polyfluoropolyether segment is linked tosilane group(s) via a functionality that includes a carbon-silicon bond,more particularly via a —C(R)₂—Si functionality where R is independentlyhydrogen or a C₁₋₄ alkyl group (preferably R is hydrogen), and mostparticularly, via a —(C(R)₂)_(k)—C(R)_(n)—Si functionality where k is atleast 2 (preferably 2 to about 25, more preferably 2 to about 15, mostpreferably 2 to about 10) and again where R is independently hydrogen ora C₁₋₄ alkyl group (preferably R is hydrogen). The inclusion of—(C(R)₂)_(k)— where k is at least 2 advantageously, additionallyprovides flexural strength.

For enhanced surface properties as well as coating efficiency,preferably the polyfluoropolyether segment is a perfluorinatedpolyfluoropolyether segment. The use of polyfluoropolyether segmentsincluding perfluorinated repeating units including short chains ofcarbon, where desirably the number of carbon atoms in sequence is atmost 6, more desirably at most 4, and most desirably at most 3,additionally facilitating durability/flexibility of the appliedpolyfluoropolyether-containing coating as well as minimizing a potentialof bioaccumulation of perfluorinated moieties.

For certain embodiments, the weight average molecular weight of thepolyfluoropolyether segment is about 1000 or higher, more desirablyabout 1200 or higher and most desirably about 1800 or higher. Higherweight average molecular weights further facilitate durability as wellas minimizing a potential of bioaccumulation. Generally for ease in useand application, the weight average molecular weight of thepolyfluoropolyether segment is desirably about 6000 at most and moredesirably about 4000 at most.

Preferably the non-fluorinated cross-linking agent comprises one or morenon-fluorinated compounds, each compound having either at least twohydrolysable groups or at least one reactive functional group and atleast one hydrolysable group. Hydrolysable groups, if two or more arepresent, may be the same or different. Hydrolysable groups are generallycapable of hydrolyzing under appropriate conditions, for example underacidic or basic aqueous conditions, such that the linking agent canundergo condensation reactions. Preferably, the hydrolysable groups uponhydrolysis yield groups capable of undergoing condensation reactions. Areactive functional group may react by condensation or additionreactions or by free-radical polymerization.

The application of compositions comprising a monofunctionalpolyfluoropolyether silane and a cross-linking agent as described hereinis also advantageous in that said application allows the provision ofvery thin polyfluoropolyether-containing coatings—yet having desirablesurface properties together with advantageous structural integrity.Preferably the thickness is at most about 300 nm, more preferably atmost about 200 nm, even more preferably at most about 150 nm, and mostpreferably at most about 100 nm. For certain of these embodiments, thethickness of the polyfluoropolyether-containing coating is at leastabout 20 nm, preferably at least about 30 nm, and most preferably atleast about 50 nm.

Additional aspects of the present invention include: devices andcomponents made in accordance with aforesaid methods.

Other aspects of the present invention include a medicinal inhalationdevice or a component of a medicinal inhalation device comprising apolyfluoropolyether-containing coating bonded to at least a portion of asurface of the device or the component, respectively, saidpolyfluoropolyether-containing coating comprising a plurality ofmonofunctional polyfluoropolyether silane entities cross-linked throughnon-fluorinated cross-linking entities and saidpolyfluorpolyether-containing coating sharing at least one covalent bondwith said surface.

Dependent claims define further embodiments of the invention

The invention, in its various combinations, either in method orapparatus form, may also be characterized by the following listing ofitems:

-   1. A method of making a medicinal inhalation device comprising a    step of: applying to at least a portion of a surface of the device a    composition comprising a monofunctional polyfluoropolyether silane    and a non-fluorinated cross-linking agent.-   2. A method of making a component of a medicinal inhalation device    comprising a step of: applying to at least a portion of a surface of    the component a composition comprising a monofunctional    polyfluoropolyether silane and a non-fluorinated cross-linking    agent.-   3. A method according to item 1 or item 2, wherein the    polyfluoropolyether segment of the polyfluoropolyether silane is not    linked to the functional silane group(s) via a functionality that    includes nitrogen-silicon bond or a sulfur-silicon bond.-   4. A method according to any one of items 1 to 3, wherein the    polyfluoropolyether segment of the polyfluoropolyether silane is    linked to the functional silane group(s) via a functionality that    includes a carbon-silicon bond.-   5. A method according to item 4, wherein the polyfluoropolyether    segment of the polyfluoropolyether silane is linked to the    functional silane group(s) via a —C(R)₂—Si functionality where R is    independently hydrogen or a C₁₋₄ alkyl group.-   6. A method according to item 5, wherein the polyfluoropolyether    segment of the polyfluoropolyether silane is linked to the    functional silane group(s) via a —(CR₂)_(k)—C(R)₂—Si functionality    where k is at least 2 and where R is independently hydrogen or a    C₁₋₄ alkyl group.-   7. A method according to any one of items 1 to 6, wherein the    functional silane group comprises at least one hydrolysable group.-   8. A method according to item 7, wherein the functional silane group    comprises at least two hydrolysable groups, more particularly three    hydrolysable groups.-   9. A method according to any one of items 1 to 8, wherein the    polyfluoropolyether segment of the polyfluoropolyether is a    perfluorinated polyfluoropolyether segment.-   10. A method according to item 9, wherein in the repeating units of    the perfluorinated polyfluoropolyether segment the number of carbon    atoms in sequence is at most 6.-   11. A method according to item 10, wherein in the repeating units of    the perfluorinated polyfluoropolyether segment the number of carbon    atoms in sequence is at most 4.-   12. A method according to item 11, wherein in the repeating units of    the perfluorinated polyfluoropolyether segment the number of carbon    atoms in sequence is at most 3.-   13. A method according to any one of items 1 to 5, wherein the    polyfluoropolyether silane is of Formula Ia:

R_(f)-Q-[C(R)₂—Si(Y)_(3-x)(R^(1a))_(x)]_(y)  Ia

-   -   wherein:        -   R_(f) is a monovalent polyfluoropolyether segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   each Y is independently a hydrolysable group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2; and        -   y is 1 or 2.

-   14. A method according to item 13, wherein the polyfluoropolyether    segment, R_(f), comprises perfluorinated repeating units selected    from the group consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—,    —(CF(Z)C_(n)F_(2n)O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and    combinations thereof; wherein n is an integer from 1 to 6 and Z is a    perfluoroalkyl group, an oxygen-containing perfluoroalkyl group, a    perfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy    group, each of which can be linear, branched, or cyclic, and have 1    to 5 carbon atoms and up to 4 oxygen atoms when oxygen-containing or    oxygen-substituted and wherein for repeating units including Z the    number of carbon atoms in sequence is at most 6.

-   15. A method according to item 14, wherein n is an integer from 1 to    4 and wherein for repeating units including Z the number of carbon    atoms in sequence is at most four.

-   16. A method according to item 14 or item 15, wherein n is an    integer from 1 to 3 and wherein for repeating units including Z the    number of carbon atoms in sequence is at most three.

-   17. A method according to item 13 or item 14, the    polyfluoropolyether segment, R_(f), is terminated with a group    selected from the group consisting of C_(n)F_(2n+1)—,    C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O— wherein X′ is a hydrogen and    wherein n is an integer from 1 to 6.

-   18. A method according to item 17, wherein the polyfluoropolyether    segment, R_(f), is terminated with a group selected from the group    consisting of C_(n)F_(2n+1)—, C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O—    wherein X′ is a hydrogen and wherein n is an integer from 1 to 4.

-   19. A method according to item 18, wherein the polyfluoropolyether    segment, R_(f), is terminated with a group selected from the group    consisting of C_(n)F_(2n+1)—, C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O—    wherein X′ is a hydrogen and wherein n is an integer from 1 to 3.

-   20. A method according to any one of items 13 to 15 or item 17 or    item 18, wherein R_(f) is selected from the group consisting of    C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, CF₃O(C₂F₄O)_(p)CF₂—,    C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—, C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—,    C₃F₇O(CF₂ CF₂CF₂O)_(p)CF(CF₃)—, and CF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X—    (wherein X is CF₂—, C₂F₄—, C₃F₆—, C₄F₈—; more particularly wherein X    is CF₂—, C₂F₄—, C₃F₆—), wherein the average value of p is 3 to 50.

-   21. A method according to any one of items 13 to 20, wherein Q is    selected from the group consisting of —C(O)N(R)—(CH₂)_(k)—,    —S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—, —CH₂O—(CH₂)_(k)—,    —C(O)S—(CH₂)_(k)—, —CH₂OC(O)N(R)—(CH₂)_(k)—, and

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25.

-   22. A method according to item 21, wherein Q is selected from the    group consisting of —C(O)N(R)(CH₂)₂—, —OC(O)N(R)(CH₂)₂—,    —CH₂—O—(CH₂)₂—, or —CH₂—OC(O)N(R)—(CH₂)₂—, wherein R is hydrogen or    C₁₋₄ alkyl and y is 1.-   23. A method according to any one of items 13 to 22, wherein x is 0.-   24. A method according to item 5 or item 6 or any one of items 13 to    23, wherein R is hydrogen.-   25. A method according to item 7 or item 8 or any one of items 13 to    23 or item 24 as dependent on any one of items 13 to 23, wherein    each hydrolysable group is independently selected from the group    consisting of hydrogen, halogen, alkoxy, acyloxy, polyalkyleneoxy,    and aryloxy groups.-   26. A method according to item 25, wherein each hydrolysable group    is independently selected from the group consisting of alkoxy,    acyloxy, aryloxy, and polyalkyleneoxy groups.-   27. A method according to item 25 or item 26, wherein each    hydrolysable group is independently an alkoxy group, in particular    an alkoxy group —OR′ wherein each R′ is independently a C₁₋₆ alkyl,    in particular a C₁₋₄ alkyl.-   28. A method according to any one of items 13 to 27, wherein R_(f)    is C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, wherein the average value of p is    at least about 3, and Q-C(R)₂—Si(Y′)_(3-x)(R^(1a))_(x) is    C(O)NH(CH₂)₃Si(OR′)₃, wherein R′ is methyl or ethyl.-   29. A method according to any one of the preceding items, wherein    the weight average molecular weight of the polyfluoropolyether    segment is about 1000 or higher, in particular about 1200 or higher,    and more particularly about 1800 or higher.-   30. A method according to any one of the preceding items, wherein    the weight average molecular weight of the polyfluoropolyether    segment is about 6000 or less, in particular about 4000 or less.-   31. A method according to any one of the preceding items, wherein    the amount of polyfluoropolyether silane having a    polyfluoropolyether segment having a weight average molecular weight    less than 750 is not more than 10% by weight of total amount of    polyfluoropolyether silane, in particular not more than 5% by weight    of total amount of polyfluoropolyether silane, more particularly not    more than 1% by weight of total amount of polyfluoropolyether    silane, and most particularly 0% by weight of total amount of    polyfluoropolyether silane.-   32. A method according to any one the preceding items, wherein the    composition further comprises an organic solvent, in particular an    organic solvent selected from the group consisting of a fluorinated    solvent, a lower alcohol and mixtures thereof.-   33. A method according to any one of the preceding items, wherein    the composition further comprises an acid.-   34. A method according to any one of the preceding items, wherein    the composition further comprises water.-   35. A method according to any one of the preceding items, wherein    the cross-linking agent comprises one or more non-fluorinated    compounds, each compound being independently selected from the group    consisting of a non-fluorinated compound having at least two    hydrolysable groups and a compound having at least one reactive    functional group and at least one hydrolysable group.-   36. A method according to item 35, wherein said non-fluorinated    compound having at least two hydrolysable groups has at least three    hydrolysable groups, and more particularly said compound has four    hydrolysable groups.-   37. A method according to item 35 or item 36, wherein said    non-fluorinated compound having at least one reactive functional    group and at least one hydrolysable group has at least two    hydrolysable groups, and more particularly said compound has three    hydrolysable groups.-   38. A method according to any one of items 1 to 35, wherein the    cross-linking agent comprises a non-fluorinated compound of silicon    selected from the group consisting of a non-fluorinated silicon    compound of Formula IIa, a non-fluorinated silicon compound of    Formula IIIa and a mixture of a non-fluorinated silicon compound of    Formula IIa and a non-fluorinated silicon compound of Formula IIIa,    where a compound of Formula IIa is a non-fluorinated silicon    compound in accordance to the following Formula IIa:

Si(Y²)_(4-g)(R⁵)_(g)  IIa

and a compound of Formula IIIa is a non-fluorinated silicon compound inaccordance to the following Formula IIIa:

L-Q′C(R)₂Si(Y²)_(3-g)—(R⁵)_(g)  IIIa

-   -   where L represents a reactive functional group;    -   Q′ represents an organic divalent linking group;    -   R is independently hydrogen or a C₁₋₄ alkyl group;    -   and    -   where, for Formulas IIa and IIIa,    -   R⁵ represents a non-hydrolysable group;    -   Y² represents a hydrolysable group; and    -   g is 0, 1 or 2.

-   39. A method according to item 38, wherein g is 0 or 1, in    particular 0.

-   40. A method according to item 38 or item 39, wherein each    hydrolysable group Y² is independently an alkoxy group, in    particular an alkoxy group —OR⁶ where each R⁶ is independently a    C₁₋₄ alkyl.

-   41. A method according to any one of items 38 to 40, wherein L    represents a reactive functional group selected from the group    consisting of an amino group, an epoxy group, a mercaptan group, an    anhydride group, vinyl ether group, vinyl ester group, an allyl    group, allyl ester group, vinyl ketone group, styrene group, vinyl    amide group, acrylamide group, maleate group, fumarate group,    acrylate group and methacrylate group.

-   42. A method according to any one of items 1 to 41, wherein the    cross-linking agent comprises a compound selected from group    consisting of tetramethoxysilane; tetraethoxysilane;    tetrapropoxysilane; tetrabutoxysilane; methyl triethoxysilane;    dimethyldiethoxysilane; octadecyltriethoxysilane;    3-glycidoxypropyltrimethoxysilane; 3-glycidoxypropyltriethoxysilane;    3-aminopropyltrimethoxysilane; 3-aminopropyl-triethoxysilane;    bis(3-trimethoxysilylpropyl) amine; 3-aminopropyl    tri(methoxyethoxyethoxy) silane;    N(2-aminoethyl)3-aminopropyltrimethoxysilane;    bis(3-trimethoxysilylpropyl)ethylenediamine;    3-mercaptopropyltrimethoxysilane; 3-mercaptopropyltriethoxysilane;    3-trimethoxysilyl-propylmethacrylate;    3-triethoxysilypropylmethacrylate; bis(trimethoxysilyl) itaconate;    allyltriethoxysilane; allyltrimetoxysilane;    3-(N-allylamino)propyltrimethoxysilane; vinyltrimethoxysilane;    vinyltriethoxysilane; and mixtures thereof.

-   43. A method according to any one of the preceding items, wherein    method includes a pre-treatment step prior to the step of applying    the composition, said pre-treatment step comprising exposing said    surface to a corona discharge or an oxygen plasma.

-   44. A method according to any one of the preceding items, wherein    said surface is aluminum or an aluminum alloy, and wherein the    method further comprises a step of anodizing said surface, said step    of anodizing being performed prior to the step of applying the    composition and in a method according to item 43, said step of    anodizing being performed prior to the pre-treatment step.

-   45. A method according to any one of the preceding items, wherein    the method further comprises a step of forming a component of the    medicinal inhalation device or the component, respectively, using a    oil comprising a hydrofluoroether or a mixture of hydrofluoroethers,    said step of forming being performed being prior to the step of    applying the composition, and in a method according item 43, said    step of forming being performed prior to the pre-treatment step, and    in a method according to item 44, said step of forming being    performed prior to the step of anodizing.

-   46. A method according to item 45, wherein the hydrofluoroether is    selected from the group consisting of methyl heptafluoropropylether;    methyl nonafluorobutylether; ethyl nonafluorobutylether;    2-trifluoromethyl-3-ethoxydodecafluorohexane and mixtures thereof.

-   47. A method according to item 45 or item 46, wherein the step of    forming is deep drawing, machining or impact extruding.

-   48. A method according to any one of items 1 to 43, wherein said    surface is a non-metal surface, in particular a plastic surface.

-   49. A method according to any one of the preceding items, wherein    the composition is applied by spraying, dipping, rolling, brushing,    spreading or flow coating, in particular by spraying or dipping.

-   50. A method according to any one of the preceding items, wherein    after applying the composition, the method further comprises a step    of curing.

-   51. A method according to item 50, wherein the curing is carried out    at an elevated temperature in the range from about 40° C. to about    300° C.

-   52. A method according to any one of the preceding items, wherein    the composition is applied to said surface, such that    polyfluoropolyether-containing coating provided on said surface has    a thickness of at most about 300 nm, in particular at most about 200    nm, more particularly at most about 150 nm, and even more    particularly at most about 100 nm.

-   53. A method according to any one of the preceding items, wherein    the composition is applied to said surface, such that    polyfluoropolyether-containing coating provided on said surface has    a thickness of at least about 20 nm, in particular at least about 30    nm, and more particularly at least about 50 nm.

-   54. A method according to any one of the preceding items, where said    surface of the device or said surface of the component of the    device, as applicable, is a surface that is or will come in contact    with a medicament or a medicinal formulation during storage or    delivery from the medicinal inhalation device.

-   55. A method according to any one of the preceding items, where said    surface of the device or said surface of the component of the    device, as applicable, is a surface that comes in contact with a    movable component of the device or is a surface of a movable    component of the device.

-   56. A method according to any one of the preceding items, wherein    the method is free of a step of pre-coating said surface prior to    applying the composition.

-   57. A method according to any one of the preceding items, where said    medicinal inhalation device is a metered dose inhaler or a dry    powder inhaler.

-   58. A medicinal inhalation device made according to item 1 or any    one of items 3 to 57 as directly or indirectly dependent on item 1.

-   59. A component of a medical inhalation device made according to    item 2 or any one of items 3 to 57 as directly or indirectly    dependent on item 2.

-   60. A medicinal inhalation device comprising a    polyfluoropolyether-containing coating bonded to at least a portion    of a surface of the device, said polyfluorpolyether-containing    coating comprising a plurality of monofunctional    polyfluoropolyether-silane entities cross-linked through    non-fluorinated cross-linking entities and said    polyfluorpolyether-containing coating sharing at least one covalent    bond with said surface.

-   61. A component of a medicinal inhalation device comprising a    polyfluoropolyether-containing coating bonded on at least a portion    of a surface of the component, said polyfluorpolyether-containing    coating comprising a plurality of monofunctional polyfluoropolyether    silane entities cross-linked through non-fluorinated cross-linking    entities and said polyfluorpolyether-containing coating sharing at    least one covalent bond with said surface.

-   62. A device according to item 60 or a component according to item    61, wherein the polyfluoropolyether segment of the    polyfluoropolyether silane entities is not linked to the functional    silane groups via a functionality that includes nitrogen-silicon    bond or a sulfur-silicon bond.

-   63. A device according to item 60 or item 62 as dependent on item 60    or a component according to item 61 or item 62 as dependent on item    61, wherein the polyfluoropolyether segment of the    polyfluoropolyether silane entities is linked to the functional    silane groups via a functionality that includes a carbon-silicon    bond.

-   64. A device according to item 63 as directly or indirectly    dependent on item 60, or a component according to item 63, as    directly or indirectly dependent on item 61, wherein the    polyfluoropolyether segment is linked to the functional silane    groups via a —C(R)₂—Si functionality where R is independently    hydrogen or a C₁₋₄ alkyl group.

-   65. A device according to item 64 as directly or indirectly    dependent on item 60, or a component according to item 64, as    directly or indirectly dependent on item 61, wherein the    polyfluoropolyether segment is linked to the functional silane    groups via a —(CR₂)_(k)—C(R)₂—Si functionality where k is at least 2    and where R is independently hydrogen or a C₁₋₄ alkyl group.

-   66. A device according to item 60 or any one of items 62 to 65 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 65 as directly or    indirectly dependent on item 61, wherein the polyfluoropolyether    segment of the polyfluoropolyether silane entities is a    perfluorinated polyfluoropolyether segment.

-   67. A device according to item 66 as directly or indirectly    dependent on item 60, or a component according to item 66 as    directly or indirectly dependent on item 61, wherein in the    repeating units of the perfluorinated polyfluoropolyether segment    the number of carbon atoms in sequence is at most 6.

-   68. A device according to item 67 as directly or indirectly    dependent on item 60, or a component according to item 67 as    directly or indirectly dependent on item 61, wherein the number of    carbon atoms in sequence is at most 4.

-   69. A device according to item 68 as directly or indirectly    dependent on item 60, or a component according to item 68 as    directly or indirectly dependent on item 61, wherein the number of    carbon atoms in sequence is at most 3.

-   70. A device according to item 60 or any one of items 62 to 69 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 69 as directly or    indirectly dependent on item 61, wherein the at least one covalent    bond shared with the surface is a bond in a —O—Si group.

-   71. A device according to item 60 or any one of items 62 to 70 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 70 as directly or    indirectly dependent on item 61, wherein the    polyfluoropolyether-containing coating shares a plurality of    covalent bonds with the surface.

-   72. A device according to item 60 or any one of items 62 to 64 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 64 as directly or    indirectly dependent on item 61, wherein the    polyfluoropolyether-containing coating comprises polyfluoropolyether    silane entities of the following Formula Ib:

R_(f)-Q-[C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)]_(y)  Ib

-   -   wherein:        -   R_(f) is monovalent polyfluoropolyether segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2; and        -   y is 1 or 2.

-   73. A device according to item 72 as directly or indirectly    dependent on item 60, or a component according to item 72 as    directly or indirectly dependent on item 61, wherein entities of    Formula Ib share at least one covalent bond with said surface and    wherein said at least one covalent bond is a bond to an oxygen atom    in Si(O—)_(3-x).

-   74. A device according to item 72 or item 73 as directly or    indirectly dependent on item 60, or a component according to item 72    or item 73 as directly or indirectly dependent on item 61, wherein    the polyfluoropolyether segment, R_(f), comprises perfluorinated    repeating units selected from the group consisting of    —(C_(n)F_(2n)O)—, —(CF(Z)O)—, —(CF(Z)C_(n)F_(2n)O)—,    —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, and combinations thereof;    wherein n is an integer from 1 to 6 and Z is a perfluoroalkyl group,    an oxygen-containing perfluoroalkyl group, a perfluoroalkoxy group,    or an oxygen-substituted perfluoroalkoxy group, each of which can be    linear, branched, or cyclic, and have 1 to 5 carbon atoms and up to    4 oxygen atoms when oxygen-containing or oxygen-substituted and    wherein for repeating units including Z the number of carbon atoms    in sequence is at most 6.

-   75. A device, according to item 74 as directly or indirectly    dependent on item 60, or a component according to item 74 as    directly or indirectly dependent on item 61, wherein n is an integer    from 1 to 4 and wherein for repeating units including Z the number    of carbon atoms in sequence is at most four.

-   76. A device according to item 74 or item 75 as directly or    indirectly dependent on item 60, or a component according to item 74    or item 75 as directly or indirectly dependent on item 61, wherein n    is an integer from 1 to 3 and wherein for repeating units including    Z the number of carbon atoms in sequence is at most three.

-   77. A device according to any one of items 72 to 74 as directly or    indirectly dependent on item 60, or a component according to any one    of items 72 to 74 as directly or indirectly dependent on item 61,    wherein the polyfluoropolyether segment, R_(f), is terminated with a    group selected from the group consisting of C_(n)F_(2n+1)—,    C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O— wherein X′ is a hydrogen and    wherein n is an integer from 1 to 6.

-   78. A device according to item 77 as directly or indirectly    dependent on item 60, or a component according to 77 as directly or    indirectly dependent on item 61, wherein the polyfluoropolyether    segment, R_(f), is terminated with a group selected from the group    consisting of C_(n)F_(2n+1)—, C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O—    wherein X′ is a hydrogen and wherein n is an integer from 1 to 4.

-   79. A device according to item 77 or item 78 as directly or    indirectly dependent on item 60, or a component according to 77 or    item 78 as directly or indirectly dependent on item 61, wherein the    polyfluoropolyether segment, R_(f), is terminated with a group    selected from the group consisting of C_(n)F_(2n+1)—,    C_(n)F_(2n+1)O—, and X′C_(n)F_(2n)O— wherein X′ is a hydrogen and    wherein n is an integer from 1 to 3.

-   80. A device according to any one of items 72 to 75 or item 77 or    item 78 as directly or indirectly dependent on item 60, or a    component according to one of items 72 to 75 or item 77 or item 78    as directly or indirectly dependent on item 61, wherein R_(f) is    selected from the group consisting of    C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, CF₃O(C₂F₄O)_(p)CF₂—,    C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—, C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—,    C₃F₇O(CF₂ CF₂CF₂O)_(p)CF(CF₃)—, and CF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X—    (wherein X is CF₂—, C₂F₄—, C₃F₆—, C₄F₈—; more particularly wherein X    is CF₂—, C₂F₄—, C₃F₆—), wherein the average value of p is 3 to 50.

-   81. A device according to any one of items 72 to 80 as directly or    indirectly dependent on item 60, or a component according to any one    of items 72 to 80 as directly or indirectly dependent on item 61,    wherein Q is selected from the group consisting of    —C(O)N(R)—(CH₂)_(k)—, —S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—,

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25.

-   82. A device according to item 81 as directly or indirectly    dependent on item 60, or a component according to item 81 as    directly or indirectly dependent on item 61, wherein Q is selected    from the group consisting of —C(O)N(R)(CH₂)₂—, —OC(O)N(R)(CH₂)₂—,    CH₂—O(CH₂)₂—, or —CH₂—OC(O)N(R)—(CH₂)₂—, wherein R is hydrogen or    C₁₋₄ alkyl and y is 1.-   83. A device according to any one of items 72 to 82 as directly or    indirectly dependent on item 60, or a component according to any one    of items 72 to 82 as directly or indirectly dependent on item 61,    wherein x is 0.-   84. A device according to any one of items 64, 65, 72 to 83 as    directly or indirectly dependent on item 60, or a component    according to any one of items 64, 65, 72 to 83 as directly or    indirectly dependent on item 61, wherein R is hydrogen.-   85. A device according to any one of items 72 to 84 as directly or    indirectly dependent on item 60, or a component according to any one    of items 72 to 84 as directly or indirectly dependent on item 61,    wherein R_(f) is C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, where the average    value of p is at least about 3, and Q-C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)    is C(O)NH(CH₂)₃Si(O—)₃.-   86. A device according to item 60 or any one of items 62 to 85 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 85 as directly or    indirectly dependent on item 61, wherein the weight average    molecular weight of the polyfluoropolyether segment is about 1000 or    higher, in particular about 1200 or higher, and more particularly    about 1800 or higher.-   87. A device according to item 60 or any one of items 62 to 86 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 86 as directly or    indirectly dependent on item 61, wherein the weight average    molecular weight of the polyfluoropolyether segment is about 6000 or    less, in particular about 4000 or less.-   88. A device according to item 60 or any one of items 62 to 87 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 87 as directly or    indirectly dependent on item 61, wherein the    polyfluoropolyether-containing coating has a thickness of at most    about 300 nm, in particular at most about 200 nm, more particularly    at most about 150 nm, and even more particularly at most about 100    nm-   89. A device according to item 60 or any one of items 62 to 88 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 88 as directly or    indirectly dependent on item 61, wherein the    polyfluoropolyether-containing coating has a thickness of at least    about 20 nm, in particular at least about 30 nm, and more    particularly at least about 50 nm.-   90. A device according to item 60 or any one of items 62 to 89 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 89 as directly or    indirectly dependent on item 61, wherein the non-fluorinated    cross-linking entities comprise entities selected from the group    consisting of entities of Formula IIb, entities of Formula IIIb or    mixtures of entities of Formula IIb and Formula IIIb, wherein an    entity of Formula IIb is an entity in accordance to the following    Formula IIb:

Si(O—)_(4-g)(R⁵)_(g)  IIb

and an entity of Formula IIIb is an entity in accordance to thefollowing Formula IIIb:

-L′-Q′C(R)₂Si(O—)_(3-g)—(R⁵)_(g)  IIIb

-   -   where L′ represents a derivative of a reactive functional group;    -   Q′ represents an organic divalent linking group;    -   each R is independently hydrogen or a C₁₋₄ alkyl group, and    -   where, for Formulas IIb and IIIb,    -   R⁵ represents a non-hydrolysable group; and    -   g is 0, 1 or 2.

-   91. A device according to item 90 as directly or indirectly    dependent on item 60, or a component according to item 90 as    directly or indirectly dependent on item 61, wherein g is 0 or 1, in    particular 0.

-   92. A device according to item 90 or item 91 as directly or    indirectly dependent on item 60, or a component according to item 90    or item 91 as directly or indirectly dependent on item 61, wherein    L′ represents a derivative of a reactive functional group, said    group selected from the group consisting of an amino group, an epoxy    group, a mercaptan group, an anhydride group, vinyl ether group,    vinyl ester group, allyl group, allyl ester group, vinyl ketone    group, styrene group, vinyl amide group, acrylamide group, maleate    group, fumarate group, acrylate group and methacrylate group.

-   93. A device according to item 60 or any one of items 62 to 92 as    directly or indirectly dependent on item 60, or a component    according to item 61 or any one of items 62 to 92 as directly or    indirectly dependent on item 61, wherein the amount of    polyfluoropolyether silane entities having a polyfluoropolyether    segment having a weight average molecular weight less than 750 is    not more than 10% by weight of total amount of polyfluoropolyether    silane entities, in particular not more than 5% by weight of total    amount of polyfluoropolyether silane entities, more particularly not    more than 1% by weight of total amount of polyfluoropolyether silane    entities, and most particularly 0% by weight of total amount of    polyfluoropolyether silane entities.

-   94. A device or a component according to any one of items 60 to 93,    as applicable, where said surface of the device or said surface of    the component of the device, as applicable, is a surface that is or    will come in contact with a medicament or a medicinal formulation    during storage or delivery from the medicinal inhalation device.

-   95. A device or a component according to any one of items 60 to 94,    as applicable, where said surface of the device or said surface of    the component of the device, as applicable, is a surface that comes    in contact with a movable component of the device or is a surface of    a movable component of the device.

-   96. A device or a component according to any one of items 60 to 95,    as applicable, wherein the device or the component, as applicable,    is free of an undercoating.

-   97. A device or a component according to any one of items 60 to 95,    as applicable, where said medicinal inhalation device is a metered    dose inhaler or a dry powder inhaler.

98. A component according to item 59 or item 61 or any one of items 62to 96 as directly or indirectly dependent on item 61, wherein thecomponent is a component of a metered dose inhaler and the component isselected from the group consisting of an actuator, an aerosol container,a ferrule, a valve body, a valve stem and a compression spring.

-   99. A component according to item 59 or item 61 or any one of items    62 to 96 as directly or indirectly dependent on item 61, wherein the    component is a component of a dry powder inhaler and the component    is selected from the group consisting of a powder container, an    component used to open sealed powder container, a component that    defines at least in part a deagglomeration chamber, a component of a    deaglomeration system, a component that defines at least in part a    flow channel, a dose-transporting component, a component that    defines at least in part a mixing chamber, a component that defines    at least in part an actuation chamber, a mouthpiece and a nosepiece.-   100. A component according to item 59 or item 61 or any one of items    62 to 96 as directly or indirectly dependent on item 61, wherein the    component is a component of a breath-actuating device or a component    of a breath-coordinating device or a spacer or a component of a    spacer or a component of a dose counter for a medicinal inhalation    device.-   101. A device according to item 58 or item 60 or any one of items 62    to 97 as directly or indirectly dependent on item 60, wherein the    device is a metered dose inhaler and the inhaler contains a    medicinal aerosol formulation comprising a medicament and HFA 134a    and/or HFA 227.-   102. A device according to item 101, wherein the medicinal aerosol    formulation is substantially free of ethanol.-   103. A device according to item 101, wherein the medicinal aerosol    formulation is free of ethanol.-   104. A device according to any one of items 101 to 103, wherein the    medicinal aerosol formulation is substantially free of surfactant.-   105. A device according to item 104, wherein the medicinal aerosol    formulation is free of surfactant.-   106. A device according to any one of items 101 to 105, wherein the    medicinal aerosol formulation comprises a medicament that is    dispersed said formulation.-   107. A device according to any one of items 101 to 106, wherein the    medicinal aerosol formulation medicinal formulation comprises a    medicament selected from the group consisting of albuterol,    terbutaline, ipratropium, oxitropium, tiotropium, beclomethasone,    flunisolide, budesonide, mometasone, ciclesonide, cromolyn sodium,    nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine,    salmeterol, fluticasone, formoterol, procaterol, indacaterol,    TA2005, omalizumab, zileuton, insulin, pentamidine, calcitonin,    leuprolide, alpha-1-antitrypsin, interferon, triamcinolone, and    pharmaceutically acceptable salts and esters thereof and mixtures    thereof.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused individually and in various combinations. In each instance, therecited list serves only as a representative group and should not beinterpreted as an exclusive list.

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 a represents a schematic cross-sectional view of a pressurizedmetered dose inhaler known in the art and FIG. 1 b represents anenlarged view of a portion of the inhaler.

FIGS. 2 to 5 represent schematic cross-sectional views of furthermetered dose valves known in the art for use in pressurized metered doseinhalers.

DETAILED DESCRIPTION

It is to be understood that the present invention covers allcombinations of particular, suitable, desirable, favorable, advantageousand preferred aspects of the invention described herein.

For better understanding of the present invention, in the following anexemplary, well known pressurized metered dose inhaler (FIG. 1) as wellas several known metered dose valves for pressurized metered doseinhalers (FIGS. 2 to 5) will be first described. In particular, FIG. 1 ashows a metered dose dispenser (100), in particular an inhaler,including an aerosol container (1) fitted with a metered dose valve (10)(shown in its resting position).

Aerosol containers for metered dose inhalers are typically made ofaluminum or an aluminum alloy. Aerosol containers may be made of othermaterials, such as stainless steel, glass, plastic and ceramics.

Returning to FIG. 1 a, the valve is typically affixed onto the containervia a cap or ferrule (11) (typically made of aluminum or an aluminumalloy) which is generally provided as part of the valve assembly. Theillustrated valve is a commercial valve marketed under the tradedesignation SPRAYMISER by 3M Company, St. Paul, Minn., USA. As shown inFIG. 1 a, the container/valve dispenser is typically provided with anactuator (5) including an appropriate patient port (6), such as amouthpiece. For administration to the nasal cavities the patient port isgenerally provided in an appropriate form (e.g. smaller diameter tube,often sloping upwardly) for delivery through the nose. Actuators aregenerally made of a plastic, for example polypropylene or polyethylene.As can be seen from FIG. 1 a, the inner walls (2) of the container andthe outer walls of the portion(s) of the metered dose valve locatedwithin the container defined a formulation chamber (3) in which aerosolformulation (4) is contained. Depending on the particular metered dosevalve and/or filling system, aerosol formulation may be filled into thecontainer either by cold-filling (in which chilled formulation is filledinto the container and subsequently the metered dose valve is fittedonto the container) or by pressure filling (in which the metered dosevalve is fitted onto the container and then formulation is pressurefilled through the valve into the container).

An aerosol formulation typically comprises a medicament or a combinationof medicaments and liquefied propellant selected from the groupconsisting of HFA 134a, HFA 227 and mixtures thereof. Aerosolformulations may, as desired or needed, comprise other excipients, suchas surfactant, a co-solvent (e.g. ethanol), CO₂, or a particulatebulking agent. Medicament may be provided in particulate form (generallyhaving a median size in the range of 1 to 10 microns) suspended in theliquefied propellant. Alternatively medicament may be in solution (e.g.dissolved) in the formulation. In the event a combination of two or moremedicaments is included, all the medicaments may be suspended or insolution or alternatively one or more medicaments may be suspended,while one or more medicaments may be in solution. A medicament may be adrug, vaccine, DNA fragment, hormone or other treatment. The amount ofmedicament would be determined by the required dose per puff andavailable valve sizes, which are typically 25, 50 or 63 microlitres, butmay include 100 microlitres where particularly large doses are required.Suitable drugs include those for the treatment of respiratory disorders,e.g., bronchodilators, anti-inflammatories (e.g. corticosteroids),anti-allergics, anti-asthmatics, anti-histamines, and anti-cholinergicagents. Therapeutic proteins and peptides may also be employed fordelivery by inhalation. Exemplary drugs which may be employed fordelivery by inhalation include but are not limited to: albuterol,terbutaline, ipratropium, oxitropium, tiotropium, beclomethasone,flunisolide, budesonide, mometasone, ciclesonide, cromolyn sodium,nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine,salmeterol, fluticasone, formoterol, procaterol, indacaterol, TA2005,omalizumab, zileuton, insulin, pentamidine, calcitonin, leuprolide,alpha-1-antitrypsin, interferons, triamcinolone, and pharmaceuticallyacceptable salts and esters thereof such as albuterol sulfate,formoterol fumarate, salmeterol xinafoate, beclomethasone dipropionate,triamcinolone acetonide, fluticasone propionate, tiotropium bromide,leuprolide acetate and mometasone furoate.

Embodiments, described in detail below, in accordance with the presentinvention are particularly useful in regard to metered dose inhalersincluding an medicinal aerosol formulation that include low amounts ofsurfactant (0.005 wt % with respect to the formulation); or issubstantially free (less than 0.0001 wt % with respect to drug) or freeof a surfactant. Alternatively or additionally, embodiments described indetail below, are particularly useful in metered dose inhalers includinga medicinal aerosol formulation that contains low amounts of ethanol(less than 5 wt % with respect to the formulation), or is substantiallyfree (less than 0.1 wt % with respect to the formulation) or free ofethanol.

The valve shown in FIG. 1 a, better viewed in FIG. 1 b, includes ametering chamber (12), defined in part by an inner valve body (13),through which a valve stem (14) passes. The valve stem, which is biasedoutwardly by a compression spring (15), is in sliding sealing engagementwith an inner tank seal (16) and an outer diaphragm seal (17). The valvealso includes a second valve body (20) in the form of a bottle emptier.

(For the sake of clarity in the description of various metered dosevalves, in particular those including at least two valve bodies, in thefollowing a valve body defining in part the metering chamber will bereferred to as a “primary” valve body, while other types of valve body,e.g. defining a pre-metering region, a pre-metering chamber, a springcage and/or a bottle emptier will be referred to as a “secondary” valvebody.)

Returning to FIG. 1 a, aerosol formulation (4) can pass from theformulation chamber into a pre-metering chamber (22) provided betweenthe secondary valve body (20) and the primary valve body (13) through anannular space (21) between the flange (23) of the secondary valve bodyand the primary valve body. To actuate (fire) the valve, the valve stem(14) is pushed inwardly relative to the container from its restingposition shown in FIGS. 1 a and b, allowing formulation to pass from themetering chamber through a side hole (19) in the valve stem and througha stem outlet (24) to an actuator nozzle (7) then out to the patient.When the valve stem (14) is released, formulation enters into the valve,in particular into the pre-metering chamber (22), through the annularspace (21) and thence from the pre-metering chamber through a groove(18) in the valve stem past the tank seal (16) into the metering chamber(12).

As mentioned above, FIGS. 2 to 5 show other known metered dose valvesused in pMDIs. Similar to the valve shown in FIG. 1, the valves of FIGS.2 to 5 are typically fitted via a ferrule onto an aerosol containerwhereby a formulation chamber is defined by the inner walls of thecontainer and the outer walls of the portion(s) of the valve locatedwithin the container. For the sake of ease in understanding andcomparison, similar components of the respective valves are identifiedwith like reference numbers in the Figures.

FIG. 2 shows a metered dose valve (10) of a type generally similar tothat disclosed and described in U.S. Pat. No. 5,772,085 (incorporatedherein by reference). The valve is shown in its resting position andincludes a valve body (20) and a valve stem (14). The valve stem, whichis biased outwardly under the pressure of the aerosol formulationcontained within the formulation container, is provided with an innerseal and an outer seal (16 and 17). Unlike the valves in FIG. 1 andFIGS. 3 to 5, which are push-to-fire type valves, the valve here is arelease-to-fire type valve. To actuate the valve, the valve stem (14) isfirst pushed upwards into the formulation chamber (not shown), so thatthe outer seal (17) passes inwardly beyond an outlet (25) provided inthe external portion of the valve body and the inner seal (16) thenpasses inwardly and disengages from the inner walls of the valve body,thus bringing the metering chamber (12) up into the formulation chamberso that formulation can enter the metering chamber (referred to as thepriming position of the valve) and then the valve stem is releasedmoving outwardly so that the inner seal re-engages the valve body andthe outer seal then passes outwardly beyond the outlet, bringing themetering chamber in communication with the outlet, so that formulationpasses through the outlet to the patient.

FIG. 3 shows a metered dose valve (10) of the type generally similar tothat disclosed and described in WO 2004/022142 (incorporated herein byreference). The valve is shown in its resting position and includes asecondary valve body (20) and a valve stem (14) that is biased outwardlyby a compression spring (15). The valve is provided with an inner seal(16) and outer diaphragm seal (17), with the valve stem being in slidingsealing engagement with the diaphragm seal. In this valve, the secondaryvalve body is in the form of a spring cage housing having three slots(21, two visible) providing communication between the formulationchamber (not shown) and a pre-metering chamber (22). This valve includesa transitory metering chamber formed upon actuation of the valve. Duringactuation of the valve, as the valve stem (14) is pushed inwardlyrelative to the container, a metering chamber (12, not visible) isformed between a lower surface (28) of a conical portion (27) of thevalve stem (14) and an upper, sloping surface (31) of a primary valvebody (13). Aerosol formulation passes around the shoulder (30) of theconical portion of the valve stem into the forming metering chamber andas the valve stem is further pushed in the upper surface (29) of theconical portion forms a face seal with the inner seal (16), therebysealing off the metering chamber. As the valve stem is yet furtherdisplaced inwardly, formulation is allowed to pass from the meteringchamber through side holes (19) in the valve stem and through a stemoutlet (24) in the valve stem, and subsequently out to the patienttypically via an actuator nozzle (7, not shown).

FIG. 4 shows a commercial metered dose valve supplied by Bespak, BergenWay, King's Lynn, Norfolk, PE30 2JJ, UK under the trade designationBK357, in its resting position. The valve includes a secondary valvebody (20) in the form of a spring cage with two slots (21) and anopening at the top (21′) allowing communication between the formulationchamber (not shown) and a pre-metering chamber (22). The valve alsoincludes a valve stem (14), made of two components (14 a, 14 b), whichis biased outwardly by a compression spring (15) and passes through ametering chamber (12) defined in part by a primary valve body (13). Thevalve stem is in sliding sealing engagement with an inner seal (16) andan outer diaphragm seal (17). Aerosol formulation can pass from thepre-metering chamber (22) into the metering chamber (12) via side holes(33 a, 33 b) in the upper portion (14 a) of the stem (14). Similar tothe valve shown in FIG. 1, to actuate (fire) the valve, the valve stem(14) is pushed inwardly relative to the container, allowing a metereddose of formulation to pass from the metering chamber through a sidehole (19) in the valve stem and through a stem outlet (24) and thentypically through an actuator nozzle (7, not shown) out to the patient.

FIG. 5 shows a commercial metered dose valve supplied by Valois SAS,Pharmaceutical Division, Route des Falaises, 27100 le Vaudreuil, Franceunder the trade designation RCS, in its resting position. The valveincludes a secondary valve body (20) in the form of a spring cage withthree slots (21, two visible) allowing communication between theformulation chamber (not shown) and a pre-metering chamber (22). Thevalve also include a valve stem (14), made of two components (14 a, 14b), which is biased outwardly by a compression spring (15) and passesthrough a metering chamber (12) defined in part by a primary valve body(13). The valve stem is in sliding sealing engagement with an inner seal(16) and an outer diaphragm seal (17). Aerosol formulation can pass fromthe pre-metering chamber (22) into the metering chamber through a sidehole (33) and an internal channel (34) provided in the upper portion (14a) of the valve stem. Similar to the valve shown in FIG. 1, to actuate(fire) the valve, the valve stem (14) is pushed inwardly relative to thecontainer, allowing formulation to pass from the metering chamberthrough a side hole (19) in the valve stem and through a stem outlet(24) and then typically through an actuator nozzle (7, not shown) out tothe patient.

With the exception of the elastomeric seals used in metered dose valves,typically the components of such valves are made of metal (e.g.stainless steel, aluminum or aluminum alloy) or plastic. For examplecompression springs are generally made of a metal, in particularstainless steel as the conventional material. Compression springs mayalso be made of aluminum or aluminum alloy. Valve stems and valve bodiesare generally made of metal and/or plastic; as a metal conventionallystainless steel is used (other metals that may be used include aluminum,aluminum alloy and titanium) and as plastics conventionally polybutyleneterephthalate (PBT) and/or acetal are used (other polymers that may beused include polyetheretherketones, nylon, other polyesters (such astetrabutylene terephthalate), polycarbonates and polyethylene).

Favorably at least a portion of a surface, more favorably the entiresurface, of a component or components of a medicinal inhalation device(e.g. aerosol containers, actuators, ferrules, valve bodies, valve stemsor compression springs of metered dose inhalers or powder containers ofdry powder inhalers) which is or will come in contact with a medicamentor a medicinal formulation during storage or delivery from the medicinalinhalation device are treated according to methods described herein.Most favorably the entire surface of the component, including anysurface or surfaces (if present) that do not or will not come in contactwith a medicament or a medicinal formulation during storage or deliveryfrom the device, are treated according to methods described herein.Alternatively or additionally, favorably at least a portion of asurface, more favorably the entire surface, of a component or componentsof a medicinal inhalation device, which either come in contact with amovable component or are movable during storage or delivery from themedicinal inhalation device are treated according to methods describedherein. Examples of such components for metered dose inhalers includee.g. valve bodies, valve stems or compression springs of metered dosevalves.

In particular a component of a medicinal inhalation device in accordancewith the present invention or made according to methods in accordancewith the present invention is a component of a metered dose inhaler.Said component may be selected from the group consisting of aerosolcontainer, an actuator, a ferrule, a valve body (e.g. a primary and/or asecondary valve body), a valve stem and a compression spring.Alternatively a component of a medicinal inhalation device in accordancewith the present invention or made according to methods in accordancewith the present invention is a component of a dry powder inhaler. Saidcomponent may be selected from the group consisting of a component thatdefines at least in part a powder container (e.g. a multidose reservoircontainer or single dose blister or capsule), an component used to opena sealed powder container (e.g. piercer to open single dose blisters orcapsules), a component that defines at least in part a deagglomerationchamber, a component of a deaglomeration system, a component thatdefines at least in part a flow channel, a dose-transporting component(e.g. a dosing rod, dosing wheel or dosing cylinder with a recessdimensioned to accommodate a single dose of powder trapped between saidcomponent and a housing in which it moves to transport the dose), acomponent that defines at least in part a mixing chamber, a componentthat defines at least in part an actuation chamber (e.g. a holdingchamber where a dose is dispensed prior to inhalation), a mouthpiece anda nosepiece.

Embodiments in accordance with certain aspects of the present inventioninclude applying onto at least a portion of a surface of a medicinalinhalation device or a component of a medicinal inhalation device (e.g.an aerosol container of a metered dose inhaler, a metered dose valve ora component thereof, or a powder container of a dry powder inhaler), acomposition comprising a monofunctional polyfluoropolyether silane and across-linking agent.

As mentioned above, the term “monofunctional polyfluoropolyether silane”as used herein is generally understood to mean a monovalentpolyfluoropolyether segment functionalized with one or more functionalsilane groups (in particular one functional silane group or twofunctional silane groups).

In compositions for application to said surface, the silane groups ofthe monofunctional polyfluoropolyether silane favorably include at leastone hydrolysable group (e.g. hydrolysable in the presence of water,optionally under acidic or basic conditions producing groups capable ofundergoing a condensation reaction, for example silanol groups), morefavorably at least two hydrolysable groups, and most favorably threehydrolysable groups. When two or more hydrolysable groups are present,the hydrolysable groups may be the same or different. Desirably ahydrolysable group is a group selected from the group consisting ofhydrogen, halogen, alkoxy, acyloxy, aryloxy, and polyalkyleneoxy, moredesirably a group selected from the group consisting of alkoxy, acyloxy,aryloxy, and polyalkyleneoxy, even more desirably a group selected fromthe group consisting of alkoxy, acyloxy and aryloxy, and most desirablyan alkoxy group (e.g. OR′ wherein each R′ is independently a C₁₋₆ alkyl,in particular a C₁₋₄ alkyl).

Application of a composition comprising a monofunctionalpolyfluoropolyether silane and a cross-linking agent as described hereinallows for effective and efficient provision of a highly desirablepolyfluoropolyether-containing coating onto said surface of themedicinal inhalation device or said surface of a component of such adevice. In particular such a coating shows extensive bonding (e.g.covalent bonding) to said surface and cross-linking within thepolyfluoropolyether-containing coating itself, providing very desirablestructural integrity over the lifetime of the medicinal inhalationdevice.

As mentioned above, the application of compositions comprising amonofunctional polyfluoropolyether silane and a cross-linking agent asdescribed herein is also advantageous in that said application allowsthe provision of very thin polyfluoropolyether-containing coatings,which although very thin have desirable surface properties together withadvantageous structural integrity over the lifetime of the medicinalinhalation device. Preferably the thickness of thepolyfluoropolyether-containing coating is at most about 300 nm, morepreferably at most about 200 nm, even more preferably at most about 150nm, and most preferably at most about 100 nm. For certain of theseembodiments, the thickness of the polyfluoropolyether-containing coatingis at least about 20 nm, preferably at least about 30 nm, and mostpreferably at least about 50 nm.

Embodiments in accordance with other aspects of the present inventioninclude a medicinal inhalation device or a component of a medicinalinhalation device, said device or component comprising apolyfluoropolyether-containing coating bonded to at least a portion of asurface of the device or component, respectively, saidpolyfluoropolyether-containing coating comprising a plurality ofmonofunctional polyfluoropolyether-silane entities cross-linked throughnon-fluorinated cross-linking entities and saidpolyfluorpolyether-containing coating sharing at least one covalent bondwith said surface.

The at least one shared covalent bond may favorably include a bond in a—O—Si group.

Favorably the polyfluoropolyether-containing coating shares a pluralityof covalent bonds with the surface of the device or component,respectively.

As mentioned above, for enhanced stability and/or resistance to attack(e.g. by ethanol, drug, and/or other potential components of medicinalinhalation formulations) desirably the polyfluoropolyether segment isnot linked to silane groups via a functionality that includes anitrogen-silicon bond or a sulfur-silicon bond. In particular, forenhanced stability and resistance of the appliedpolyfluoropolyether-containing coating to attack, it is desirable thatpolyfluoropolyether segment is linked to silane groups via afunctionality that include a carbon-silicon bond, more particularly viaa —C(R)₂—Si functionality where R is independently hydrogen or a C₁₋₄alkyl group, and most particular, via a —(C(R)₂)_(k)—C(R)₂—Sifunctionality where k is at least 2 (preferably 2 to about 25, morepreferably 2 to about 15, most preferably 2 to about 10). The inclusionof —(C(R)₂)_(k)— where k is at least 2 advantageously, additionallyprovides flexural strength. Preferably R is hydrogen.

As mentioned above, for enhanced surface properties as well as coatingefficiency, preferably the polyfluoropolyether segment is aperfluorinated polyfluoropolyether segment. The use ofpolyfluoropolyether segments including perfluorinated repeating unitsincluding short chains of carbon, where desirably the number of carbonatoms in sequence is at most 6, more desirably at most 4, and mostdesirably at most 3, additionally facilitates durability/flexibility ofthe applied polyfluoropolyether-containing coating as well as minimizinga potential of bioaccumulation of perfluorinated moieties.

As mentioned above, for certain embodiments, the weight averagemolecular weight of the polyfluoropolyether segment is about 1000 orhigher, more desirably about 1200 or higher, and most desirably about1800 or higher. Higher weight average molecular weights furtherfacilitate durability as well as minimizing a potential ofbioaccumulation. Generally for ease in use and application, the weightaverage molecular weight of the polyfluoropolyether segment is desirablyabout 6000 at most and more desirably about 4000 at most.

Polyfluoropolyether silanes typically include a distribution ofoligomers and/or polymers. Desirably, for facilitation of structuralintegrity of polyfluoropolyether-containing coating as well asminimization of a potential of bioaccumulation, the amount ofpolyfluoro-polyether silane (in such a distribution) having apolyfluoropolyether segment having a weight average molecular weightless than 750 is not more than 10% by weight (more desirably not morethan 5% by weight, and even more desirably not more 1% by weight andmost desirably 0% of total amount of polyfluoropolyether silane in saiddistribution.

For certain favorable embodiments, the composition comprising amonofunctional polyfluoropolyether silane as described herein is acomposition comprising a monofunctional polyfluoropolyether silane ofthe Formula Ia:

R_(f)-Q-[C(R)₂—Si(Y)_(3-x)(R^(1a))_(x)]_(y)  Ia

-   -   wherein:        -   R_(f) is a monovalent polyfluoropolyether segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   each Y is independently a hydrolysable group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2; and        -   y is 1 or 2.

Application of compositions comprising polyfluoropolyether silanes inaccordance with Formula Ia in conjunction with a cross-linking agentfavorably allows the provision of medicinal inhalation devices orcomponents thereof comprising a polyfluoropolyether-containing coatingbonded (e.g. covalently bonded) onto at least a portion of surface ofthe device or component, as applicable, wherein thepolyfluoropolyether-containing coating comprises monofunctionalpolyfluoropolyether silane entities of the following Formula Ib:

R_(f)-Q-[C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)]_(y)  Ib

-   -   wherein:        -   R_(f) is monovalent polyfluoropolyether segment;        -   Q is an organic divalent or trivalent linking group;        -   each R is independently hydrogen or a C₁₋₄ alkyl group;        -   R^(1a) is a C₁₋₈ alkyl or phenyl group;        -   x is 0 or 1 or 2; and        -   y is 1 or 2.

The at least one covalent bond shared with the surface of the medicinalinhalation device or the surface of a component of a medicinalinhalation device, as applicable, may desirably include a bond to anoxygen atom in Si(O—)_(3-x).

Advantageously such polyfluoropolyether-containing coatings aretypically transparent or translucent.

The monovalent polyfluoropolyether segment, R_(f), includes linear,branched, and/or cyclic structures, that may be saturated orunsaturated, and includes two or more in-chain oxygen atoms. R_(f) ispreferably a perfluorinated group (i.e., all C—H bonds are replaced byC—F bonds). However, hydrogen atoms may be present instead of fluorineatoms provided that not more than one atom of hydrogen is present forevery two carbon atoms. When hydrogen atoms are present, preferably,R_(f) includes at least one perfluoromethyl group.

For certain embodiments, the monovalent polyfluoropolyether segment,R_(f), comprises perfluorinated repeating units selected from the groupconsisting of —(C_(n)F_(2n))—, —(C_(n)F_(2n)O)—, —(CF(Z))—, —(CF(Z)O)—,—(CF(Z)C_(n)F_(2n)O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, andcombinations thereof; wherein n is an integer from 1 to 6; Z is aperfluoroalkyl group, an oxygen-containing perfluoroalkyl group, aperfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy group,each of which can be linear, branched, or cyclic, and have 1 to 5 carbonatoms and up to 4 oxygen atoms when oxygen-containing oroxygen-substituted. For units comprising Z it is desirable that thetotal number of carbon atoms in sequence per unit is at most 6 (moredesirably at most 4, and most desirably at most 3). Being oligomeric orpolymeric in nature, these compounds exist as mixtures and are suitablefor use as such. The perfluorinated repeating units may be arrangedrandomly, in blocks, or in an alternating sequence. Favorably, thepolyfluoropolyether segment comprises perfluorinated repeating unitsselected from the group consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—,—(CF(Z)C_(n)F_(2n)O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, andcombinations thereof; and more favorably perfluorinated repeating unitsselected from the group consisting of —(C_(n)F_(2n)O)—,—(C_(n)F_(2n)CF(Z)O)—, —(CF(Z)O)—, and combinations thereof. For certainof these embodiments, n is an integer from 1 to 4; or 1 to 3; or 1 or 2.For certain of these embodiments, Z is a —CF₃ group.

For certain embodiments, R_(f) is terminated with a group selected fromthe group consisting of C_(n)F_(2n+1)—, C_(n)F_(2n+1)O—, andX′C_(n)F_(2n)O— wherein X′ is a hydrogen. For certain of theseembodiments, the terminal group is C_(n)F_(2n+1)— or C_(n)F_(2n+1)O—wherein n is an integer from 1 to 6, more favorably 1 to 4, mostfavorably 1 to 3. For certain of these embodiments, the approximateaverage structure of R_(f) is C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,CF₃O(C₂F₄O)_(p)CF₂—, C₃F₇O(CF(CF₃)CF₂O)_(p)CF₇CF₂—,C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—, or C₃F₇O(CF₂ CF₂CF₂O)_(p)CF(CF₃)—, orCF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X— (wherein X is CF₂—, C₂F₄—, C₃F₆—, C₄F₈—;more favorably wherein X is CF₂—, C₂F₄—, C₃F₆—) wherein the averagevalue of p is 3 to 50.

The above structures are approximate average structures where pdesignate the number of randomly distributed perfluorinated repeatingunits. Further, as mentioned above polyfluoropolyether silanes describedherein typically include a distribution of oligomers and/or polymers, sop may be non-integral and where the number is the approximate average isover this distribution.

The organic divalent or trivalent linking group, Q, can include linear,branched, or cyclic structures that may be saturated or unsaturated. Theorganic divalent or trivalent linking group, Q, optionally contains oneor more heteroatoms selected from the group consisting of sulfur,oxygen, and nitrogen, and/or optionally contains one or more functionalgroups selected from the group consisting of esters, amides,sulfonamides, carbonyl, carbonates, ureylenes, and carbamates. Again forflexural strength Q favorably includes a segment with not less than 2carbon atoms, said segment of Q being directly bonded to the —C(R)₂—group of the silane-containing moiety (i.e. for Formula Ia—C(R)₂—Si(Y)_(3-x)(R^(1a))_(x) and for Formula Ib—C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)). For such embodiments generally Qincludes not more than about 25 carbon atoms. Q is preferablysubstantially stable against hydrolysis and other chemicaltransformations, such as nucleophilic attack. When more than one Qgroups are present, the Q groups can be the same or different.

For certain embodiments, including any one of the above embodiments, Qincludes organic linking groups such as —C(O)N(R)—(CH₂)_(k)—,—S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—, —CH₂O—(CH₂)_(k)—, —C(O)S—(CH₂)_(k)—,—CH₂OC(O)N(R)—(CH₂)_(k)—, and

wherein R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25. For certainof these embodiments, k is 2 to about 15 or 2 to about 10.

Favorably Q is a divalent linking group, and y is 1. In particular, Q isfavorably a saturated or unsaturated hydrocarbon group including 1 toabout 15 carbon atoms and optionally containing 1 to 4 heteroatomsand/or 1 to 4 functional groups. For certain of these embodiments, Q isa linear hydrocarbon containing 1 to about 10 carbon atoms, optionallycontaining 1 to 4 heteroatoms and/or 1 to 4 functional groups. Forcertain of these embodiments, Q contains one functional group. Forcertain of these embodiments, Q is preferably —C(O)N(R)(CH₂)₂—,—OC(O)N(R)(CH₂)₂—, —CH₂—O—(CH₂)₂—, or —CH₂—OC(O)N(R)—(CH₂)₂—, wherein Ris hydrogen or C₁₋₄ alkyl.

For certain favorable embodiments, including any embodiment describedherein where R is present, R is hydrogen.

Favorably x in the silane-containing moiety (i.e. for Formula Ia—C(R)₂—Si(Y)_(3-x)(R^(1a))_(x) and for Formula Ib—C(R)₂—Si(O—)_(3-x)(R^(1a))_(x)) is 0.

The hydrolyzable groups, Y, of Formula Ia may be the same or differentand are capable of hydrolyzing, for example, in the presence of water,optionally under acidic or basic conditions, producing groups capable ofundergoing a condensation reaction, for example silanol groups.Desirably, each Y of Formula Ia is independently a group selected fromthe group consisting of hydrogen, halogen, alkoxy, acyloxy, aryloxy, andpolyalkyleneoxy, more desirably each Y is independently a group selectedfrom the group consisting of alkoxy, acyloxy, aryloxy, andpolyalkyleneoxy, even more desirably each Y is independently a groupselected from the group consisting of alkoxy, acyloxy and aryloxy, andmost desirably each Y is independently an alkoxy group.

For certain embodiments, including any relevant embodiment describedherein:

-   -   Favorably alkoxy is —OR′, and acyloxy is —OC(O)R′, wherein each        R′ is independently a lower alkyl group, optionally substituted        by one or more halogen atoms. For certain embodiments, R′ is        preferably C₁₋₆ alkyl and more preferably C₁₋₄ alkyl. R′ can be        a linear or branched alkyl group.    -   Favorably aryloxy is —OR″ wherein R″ is aryl optionally        substituted by one or more substituents independently selected        from halogen atoms and C₁₋₄ alkyl optionally substituted by one        or more halogen atoms. For certain embodiments, R″ is preferably        unsubstituted or substituted C₆₋₁₂ aryl and more preferably        unsubstituted or substituted    -   C₆₋₁₀ aryl.    -   Favorably polyalkyleneoxy is —O—(CHR⁴—CH₂O)_(q)—R³ wherein R³ is        C₁₋₄ alkyl, R⁴ is hydrogen or methyl, with at least 70% of R⁴        being hydrogen, and q is 1 to 40, preferably 2 to 10.

For certain particularly favored embodiments, including any one of theabove embodiments including a compound in accordance with Formula Ia,R_(f) is C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, wherein the average value of pis at least about 3, and Q-C(R)₂—Si(Y)_(3-x)(R^(1a))_(x) isC(O)NH(CH₂)₃Si(OR′)₃ wherein R′ is methyl or ethyl. For certainparticular favored embodiments, including any one of the aboveembodiments including an entity in accordance with Formula Ib, R_(f) isC₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, where the average value of p is at leastabout 3, and Q-C(R)₂—Si(O—)_(3-x)(R^(1a))_(x) is C(O)NH(CH₂)₃Si(O—)₃.For certain of these embodiments, average value of p is about 3 to about25, more favorably average value of p is at least about 4.3, even morefavorably at least about 5.5 and most favorably at least about 9.2.

Compounds in accordance with Formula Ia as described above can besynthesized using standard techniques. For example, commerciallyavailable or readily synthesized perfluoropolyether esters (orfunctional derivatives thereof) can be combined with a functionalizedalkoxysilane, such as a 3-aminopropylalkoxysilane, according to U.S.Pat. No. 3,646,085 (Bartlett et al.).

Compositions comprising a monofunctional polyfluoropolyether silane asdescribed herein further comprise a non-fluorinated cross-linking agentthat is capable of engaging in a cross-linking reaction. As mentionedabove, preferably such a cross-linking agent comprises one or morenon-fluorinated compounds, each compound being independently selectedfrom the group consisting of:

-   a compound having at least two hydrolysable groups (more preferably    at least three hydrolysable groups, and most preferably four    hydrolysable groups) and-   a compound having at least one reactive functional group and at    least one hydrolysable group (more preferably at least one reactive    functional group and at least two hydrolysable groups, and most    preferably at least one reactive functional group and three    hydrolysable groups). A higher number of hydrolysable groups per    cross-linking compound facilitates desirable cross-linking within    the polyfluoropolyether-containing coating itself, and hence    structural integrity of the coating over the lifetime of the    medicinal inhalation device. Hydrolysable groups, if two or more are    present, may be the same or different. Hydrolysable groups are    generally capable of hydrolyzing under appropriate conditions, for    example under acidic or basic aqueous conditions, such that the    linking agent can undergo condensation reactions. Preferably, the    hydrolysable groups upon hydrolysis yield groups capable of    undergoing condensation reactions. Typical and preferred examples of    hydrolysable groups include those as described above, e.g. with    respect to Formula Ia. Preferably, hydrolysable groups are    independently an alkoxy, —OR⁶, more preferably an alkoxy where R⁶ is    a C₁₋₄ alkyl. A reactive functional group may react by condensation    or addition reactions (e.g. an amino group, an epoxy group, a    mercaptan group or an anhydride group) or by free-radical    polymerization (e.g. a vinyl ether group, a vinyl ester group, an    allyl group, an allyl ester group, a vinyl ketone group, a styrene    group, a vinyl amide group, an acrylamide group, a maleate group, a    fumarate group, an acrylate group or a methacrylate group).

Advantageously such a cross-linking agent comprises one or morenon-fluorinated compounds of silicon having either at least twohydrolysable groups or at least one reactive functional group and atleast one hydrolysable per molecule. Preferably such a non-fluorinatedcompound of silicon is a compound in accordance to Formula IIa orFormula IIIa:

Si(Y²)_(4-g)(R⁵)_(g)  IIa

-   -   where R⁵ represents a non-hydrolysable group;    -   Y² represents a hydrolysable group; and    -   g is 0, 1 or 2;

L-Q′C(R)₂—Si(Y²)_(3-g)(R⁵)_(g)  IIIa

-   -   where L represents a reactive functional group;    -   Q′ represents an organic divalent linking group;    -   R is independently hydrogen or a C₁₋₄ alkyl group;    -   R⁵ represents a non-hydrolysable group;    -   Y² represents a hydrolysable group; and    -   g is 0, 1 or 2.

Cross-linking agents may favorably comprise a mixture of anon-fluorinated silicon compound in accordance with Formula IIa and anon-fluorinated silicon compound in accordance with Formula IIIa.

The non-hydrolysable group R⁵ is generally not capable of hydrolyzingunder the conditions used during application of the compositioncomprising the monofunctional polyfluoropolyether silane and a relevantcross-linking agent. For example, the non-hydrolysable group R⁵ may beindependently selected from a hydrocarbon group. If g is 2, thenon-hydrolysable groups may the same or different. Preferably g is 0 or1, more preferably g is 0. Y² represents a hydrolysable group asdescribed above, and as described hydrolysable groups may be the same ordifferent. Preferably, the hydrolysable groups upon hydrolysis yieldsilanol groups capable of undergoing condensation reactions. Preferably,hydrolysable groups are independently an alkoxy, —OR⁶, more preferablyan alkoxy where R⁶ is a C₁₋₄ alkyl.

Representative examples of favorable non-fluorinated silicon compoundsin accordance with Formula IIa for use in a cross-linking agent includetetramethoxysilane, tetraethoxysilane, tetrapropoxysilane,tetrabutoxysilane, methyl triethoxysilane, dimethyldiethoxysilane,octadecyltriethoxysilane, and mixtures thereof. Preferably thecross-linking agent comprises C₁-C₄ tetra-alkoxy derivatives of silicon,more preferably the cross-linking agent comprises tetraethoxysilane.

Regarding Formula III, R is preferably hydrogen. Typical examples of thedivalent linking group Q′ include those described with respect toFormula I. Linking groups Q′ for Formula III are favorably selected fromthe group consisting of alkylene (preferably containing 2 to 20, morepreferably 2 to 10 carbon atoms), oxyalkylene (preferably containing 2to 20 carbon atoms and 1 to 10 oxygen atoms), aminoalkylene (preferablycontaining 2 to 20 carbon atoms and 1 to 10 nitrogen atoms) andcarbonyloxyalkylene (preferably containing 3 to 20 carbons atoms).

L in Formula IIIa represents a reactive functional group that may reactby condensation or addition reactions or by free-radical polymerizationreactions. Desirably L is selected from the group consisting of an aminogroup, an epoxy group, a mercaptan group, an anhydride group, vinylether group, vinyl ester group, allyl group, allyl ester group, vinylketone group, styrene group, vinyl amide group, acrylamide group,maleate group, fumarate group, acrylate group and methacrylate group.

Representative examples of favorable non-fluorinated silicon compoundsin accordance with Formula IIIa for use in a cross-linking agent include3-glycidoxy-propyltrimethoxysilane; 3-glycidoxypropyltriethoxysilane;3-aminopropyl-trimethoxysilane; 3-aminopropyltriethoxysilane;bis(3-trimethoxysilylpropyl) amine; 3-aminopropyltri(methoxyethoxyethoxy) silane; N(2-aminoethyl)3-aminopropyltrimethoxysilane;bis(3-trimethoxysilylpropyl)ethylenediamine;3-mercaptopropyltrimethoxysilane; 3-mercaptopropyltriethoxysilane;3-trimethoxysilyl-propylmethacrylate; 3-triethoxysilypropylmethacrylate;bis(trimethoxysilyl) itaconate; allyltriethoxysilane;allyltrimetoxysilane; 3-(N-allylamino)propyltrimethoxysilane;vinyltrimethoxysilane; vinyltriethoxysilane; and mixtures thereof.

The amounts by weight of the monofunctional polyfluoropolyether silaneto the non-fluorinated cross-linking agent can change from about 10:1 toabout 1:100, preferably from about 1:1 to about 1:50 and most preferablyfrom about 1:2 to about 1:20.

Generally the use of a cross-linking agent allows for cross-linking ofmonofunctional polyfluoropolyether silane compounds described herein,while at the same time facilitating attachment (e.g. covalent bonding)of polyfluoropolyether-containing coatings described herein andpotentially providing an economic benefit (e.g. allowing a reduction inthe amount of relatively expensive fluorosilane to be applied). Inparticular for certain embodiments including a cross-linking agentcomprising one or more compounds having at least one reactive functionalgroup and at least one hydrolysable group per molecule, the use of suchagents can advantageously facilitate and/or enhance attachment andcovalent bonding of polyfluoropolyether-containing coatings as describedherein onto a non-metal surface (e.g. a plastic surface) of a medicinalinhalation device or a component (e.g. onto components made of aplastic, such as a MDI actuator made of polyethylene or polypropylene ora metered dose valve component (e.g. a valve body or a valve stem) madeof acetal, nylon, a polyester (e.g. PBT; TBT), a PEEK, a polycarbonateor a polyalkylene).

Coatings provided through the application of a composition comprising amonofunctional polyfluoropolyether silane and a cross-linking agentcomprising a compound in accordance with Formula IIa, desirably containentities in accordance with the Formula IIb:

Si(O—)_(4-g)(R⁵)_(g)  IIb

where R⁵ represents a non-hydrolysable group (as described above), and gis 0, 1, 2 (preferably 0 or 1, more preferably 0). The at least onecovalent bond shared with the surface of the medicinal inhalation deviceor the surface of a component of a medicinal inhalation device, asapplicable, may desirably include a bond to an oxygen atom inSi(O—)_(4-g).

Similarly coatings provided through the application of a compositioncomprising a monofunctional polyfluoropolyether silane and across-linking agent comprising a compound in accordance with FormulaIIIa, desirably contain entities in accordance with the Formula IIIb:

-L′-Q′C(R)₂Si(O—)_(3-g)—(R⁵)_(g)  IIIb

where R⁵ represents a non-hydrolysable group (as described above), and gis 0, 1, 2 (preferably 0 or 1, more preferably 0); Q′ represents anorganic divalent linking group (as described above); each R isindependently hydrogen or a C₁₋₄ alkyl group (preferably hydrogen) andL′ represents a derivative of a reactive functional group (e.g. aderivative of a reactive functional group L described above resultingfrom a condensation reaction or an addition reaction or a free-radialpolymerization reaction). The at least one covalent bond shared with thesurface of the medicinal inhalation device or the surface of a componentof a medicinal inhalation device, as applicable, may advantageouslyinclude a bond to L′.

Polyfluoropolyether-containing coatings described herein may favorablycomprise a mixture of entities in accordance with Formula Jib andentities in accordance with Formula IIIb.

For certain embodiments, the monofunctional polyfluoropolyether silaneis desirably applied as a composition comprising the monofunctionalpolyfluoropolyether silane, the cross-linking agent and an organicsolvent. The organic solvent or blend of organic solvents used typicallyis capable of dissolving at least about 0.01 percent by weight of themonofunctional polyfluoropolyether silane, in particular one or moresilanes of the Formula Ia. It is desirable that the solvent or mixtureof solvents have a solubility for water of at least about 0.1 percent byweight, and for certain of these embodiments, a solubility for acid ofat least about 0.01 percent by weight.

Suitable organic solvents, or mixtures of solvents can be selected fromaliphatic alcohols, such as methanol, ethanol, and isopropanol; ketonessuch as acetone and methyl ethyl ketone; esters such as ethyl acetateand methyl formate; ethers such as diethyl ether, diisopropyl ether,methyl t-butyl ether and dipropyleneglycol monomethylether (DPM);hydrocarbon solvents such as alkanes, for example, heptane, decane, andparaffinic solvents; fluorinated hydrocarbons such as perfluorohexaneand perfluorooctane; partially fluorinated hydrocarbons, such aspentafluorobutane; hydrofluoroethers such as methyl perfluorobutyl etherand ethyl perfluorobutyl ether. For certain embodiments, including anyone of the above embodiments, the organic solvent is a fluorinatedsolvent, which includes fluorinated hydrocarbons, partially fluorinatedhydrocarbons, and hydrofluoroethers. For certain of these embodiments,the fluorinated solvent is a hydrofluoroether. For certain of theseembodiments, the hydrofluoroether is methyl perfluorobutyl ether. Forcertain embodiments, including any one of the above embodiments exceptwhere the organic solvent is a fluorinated solvent, the organic solventis a lower alcohol. For certain of these embodiments, the lower alcoholis selected from the group consisting of methanol, ethanol, isopropanol,and mixtures thereof. For certain of these embodiments, the loweralcohol is ethanol.

For certain embodiments, including any one of the above embodimentswhere the organic solvent is a lower alcohol, the composition favorablyfurther comprises an acid. For certain of these embodiments, the acid isselected from the group consisting of acetic acid, citric acid, formicacid, triflic acid, perfluorobutyric acid, sulfuric acid, andhydrochloric acid. For certain of these embodiments, the acid ishydrochloric acid.

For certain embodiments, e.g. compositions including a hydrolysablegroup, the composition may further comprise water.

Compositions comprising a monofunctional polyfluoropolyether silane anda cross-linking agent, including any one of the above describedembodiments, can be applied to at least a portion of the surface of themedicinal inhalation device or the component thereof using a variety ofcoating methods. Such methods include but are not limited to spraying,dipping, spin coating, rolling, brushing, spreading and flow coating.Preferred methods for application include spraying and dipping. Forcertain embodiments the composition, in any one of its above describedembodiments, is applied by dipping at least a portion of the substrateto be coated in said composition. Alternatively, for certainembodiments, the composition, in any one of its above describedembodiments, is applied by spraying at least a portion of the substrateto be coated with said composition. For the preparation of a durablecoating, sufficient water should be present to cause hydrolysis of thehydrolysable groups described above e.g. so that condensation to form—O—Si groups takes place, and thereby curing takes place. The water canbe present either in the treating composition or adsorbed to thesubstrate surface, for example. Typically, sufficient water is presentfor the preparation of a durable coating if the application is carriedout at room temperature in an atmosphere containing water, for example,an atmosphere having a relative humidity of about 30% to about 80%.

Application is typically carried out by contacting the substrate withthe treating composition, generally at room temperature (typically about20° C. to about 25° C.). Alternatively treating composition can beapplied to a substrate that is pre-heated at a temperature of forexample between 60° C. and 150° C. Following application the treatedsubstrate allow to dry and cure at ambient temperature (typically about20° C. up to but not including 40° C.). Alternatively, as desired orneeded, the treated substrate can be dried and cured at elevatedtemperatures (e.g. at 40° C. to 300° C.) and for a time sufficient todry and cure. If desired or needed, the treating composition may furthercomprise a thermal initiator. Examples of suitable thermal initiatorsinclude, among others, organic peroxides in the form of diacylperoxides, peroxydicarbonates, alkyl peresters, dialkyl peroxides,perketals, ketone peroxides and alkyl hydroperoxides. Specific examplesof such thermal initiators are dibenzoyl peroxide, tert-butylperbenzoate and azobisisobutyronitrile. Alternatively or in additionthereto, following application of the treating composition the treatedsubstrate may be cured (again if desired or needed) by irradiation (e.g.means of UV-irradiators, etc.). Hereto the treating compositiontypically further comprises a photo-initiator, and curing is performedin a manner known per se, depending on the type and presence,respectively of the photo-initiator used in the treating composition.Photo-initiators for irradiation curing are commercially available andinclude e.g. benzophenone; photo-initiators available under the tradedesignation IRGACURE from Ciba-Geigy (e.g., IRGACURE 184(1-hydroxycyclohexyl phenyl ketone) and IRGACURE 500(1-hydroxycyclohexyl phenyl ketone, benzophenone); and photo-initiatorsavailable under the trade designation DARPCUR from Merck.

It is particularly advantageous for certain embodiments of methodsdescribed herein where the composition comprises a monofunctionalpolyfluoropolyether silane and a non-fluorinated cross-linking agentcomprising one or more non-fluorinated compounds, each compound havingat least one reactive functional group as described herein, to perform athermal curing step, or irradiation-induced curing step, or a two-foldcuring (e.g. an irradiation-induced curing followed by a thermal curingor a thermal curing followed by a second thermal curing). Theappropriate selection of curing depends on the particular compound(s)used in the cross-linking agent and the particular reactive functionalgroup(s) of the compound(s). For example a substrate treated with such acomposition including a compound having a reactive amino functionalgroup (e.g., 3-aminopropyltrimethoxysilane;3-aminopropyltriethoxysilane, bis(3-trimethoxysilylpropyl) amine;3-aminopropyl tri(methoxyethoxyethoxy) silane; N(2-aminoethyl)3-aminopropyltrimethoxysilane; and,bis(3-trimethoxysilylpropyl)ethylenediamine) are typically subjected toa thermal curing. A substrate treated with a composition including acompound having a reactive functional selected from the group consistingof an epoxy group, mercaptan group, anhydride group (e.g.,3-glycidoxypropyltrimethoxysilane, 3-glycidoxypropyltriethoxysilane,3-mercaptopropyltrimethoxysilane, and 3-mercaptopropyltriethoxysilane)may be subjected to a thermal curing or an irradiation-induced curing(preferably a thermal curing). A substrate treated with a compositionincluding a compound having a reactive functional group which react byfree-radial polymerization (e.g., 3-trimethoxysilyl-propylmethacrylate,3-triethoxysilylpropylmethacrylate, bis(trimethoxysilyl) itaconate,allyltriethoxysilane, allyltrimetoxysilane,3-(N-allylamino)propyltrimethoxysilane, vinyltrimethoxysilane andvinyltriethoxysilane) are typically subjected to an irradiation-inducedcuring, but also may be, alternatively (and in some embodiments morefavorably), subjected to a thermal curing. It will be appreciated thatthe respective treating composition may include, as desired or needed,an appropriate initiator for the particular type of curing, e.g. aphoto-initiator and/or a thermal initiator. Suitable photo-initiator andthermal initiators are described above. Typically an initiator will beadded in an amount between 0.1 and 2% by weight based on the weight ofthe compound(s) of the cross-linking agent.

For effective and efficient coating of components of medicinalinhalation devices, in particular complex-shaped components havingrestricted/constrained cavities or channels, the use of cross-linkingagents that are cured under ambient temperatures and/or elevatedtemperatures are particularly advantageous.

A post-treatment process may include a rinsing step (e.g. before orafter drying/curing, as desired or needed) to remove excess material,followed by a drying step.

Methods described herein may include a pre-treatment step prior to thestep of applying to at least a portion of a surface of the medicinalinhalation device or to at least a portion of a surface of the componentof a medicinal inhalation device, as applicable, a compositioncomprising a monofunctional polyfluoropolyether silane and a crosslinking agent as described herein. Favorably the pre-treatment stepcomprises exposing said surface to an oxygen plasma, in particular anoxygen plasma under conditions of ion bombardment (i.e. generating anion sheath and having the substrate to be coated located within the ionsheath during said oxygen plasma treatment). Alternatively and morefavorably, the pre-treatment step comprises exposing said surface to acorona discharge. Such pre-treatments may desirably facilitate theprovision of extensive bonding of the polyfluoropolyether-containingcoating to the surface of the medicinal inhalation device or the surfaceof a component of the medicinal inhalation device, as applicable, andthus facilitate overall structural integrity of the coating over thelifetime of the device. Such pre-treatments may be advantageous, whencoating plastic surfaces (e.g. components made of plastic, such as MDIvalve components or actuators), more particularly when coating suchplastic surfaces with compositions that do not include a cross-linkingagent including a compound having a reactive functional group asdescribed herein. Corona discharge treatment is particular advantageousin that it is highly effective and efficient in activating surfaceswhile at the same time allowing for quick, easy and cost-efficientpre-treatment on large scale.

In certain embodiments of methods described herein, the surface isaluminum or an aluminum alloy. For example, in methods applying to atleast a portion of a surface of a component of a medicinal inhalationdevice a composition comprising a monofunctional polyfluoropolyethersilane and a cross linking agent as described herein, the component maybe made of aluminum or an aluminum alloy. Examples of such componentsinclude components of MDIs, such as canisters, ferrules, and metereddose valve components (such as valve bodies and valves stems). For suchmethods favorably such methods further comprise a step of anodizing saidsurface, where such step of anodizing is performed prior to the step ofapplying the composition and if applicable, such step of anodizing isperformed prior to a pre-treatment step as described. Anodizing isbeneficial in hardening the aluminum or aluminum alloy as well asremoving or minimizing surface imperfections resulting from fabrication(such as deep drawing) and facilitating the naturally occurring oxideprocess, all of which further facilitate overall durability of thecomponent as well as application efficiency of and subsequent structuralintegrity of the applied polyfluoropolyether-containing coating.

Methods described herein may further include a step of pre-washing saidsurface to clean and/or degrease the surface (e.g. to removepetroleum-based drawing oil typically used in deep-drawing metalcomponents like MDI canisters or valve components). Such a pre-washingstep may be performed with a solvent, in particular an organic solventsuch as trichloroethylene, acetone or ethanol, or alternatively with anaqueous detergent solution followed by rinsing with water, and ifapplicable drying. Such a pre-washing step would typically be performedprior to the step of applying a composition comprising a monofunctionalpolyfluoropolyether silane as described herein. If applicable, such apre-washing step may be performed prior to any pre-treatment step.Further and again if applicable, such a pre-washing step may beperformed prior to any anodizing step.

It has been found advantageous to form a component (in particular ametal component) of a medicinal inhalation device (in particular to formby deep-drawing, machining, or impact extrusion) using an oil comprisinga hydrofluoroether or a mixture of hydrofluoroethers. For such formedcomponents it has been determined that a pre-washing step can generallybe avoided, which is advantageous in processing/manufacturing efficientas well as cost-efficient. Favorably the hydrofluoroether is selectedfrom the group consisting of methyl heptafluoropropylether; methylnonafluorobutylether; ethyl nonafluorobutylether;2-trifluoromethyl-3-ethoxydodecafluorohexane and mixtures thereof.

Methods described herein are desirably free of a step of pre-coating thesurface of medicinal inhalation device or the surface of the componentof the medicinal inhalation device, respectively, prior to applying thecomposition comprising a monofunctional polyfluoropolyether silane and across linking agent according to any embodiment described herein.Medicinal inhalation devices and components of such devices comprising apolyfluoropolyether-containing coating covalently bonded to at least aportion of a surface of the device or the component, respectively, asdescribed herein are desirably free of an undercoating.

Besides the provision of medicinal inhalation devices and componentsthereof having desirable surface properties and structural integrity,methods of providing such medicinal inhalation devices and components asdescribed herein are advantageous in their versatility and/or broadapplicability to making various components of such medicinal inhalationdevices, such components having significantly differing shapes and formsmade of significantly differing materials. For example methods describedherein can be advantageously used to provide a coating on at least aportion of the interior surface (preferably on the entire interiorsurface, more preferably the entire surface) of an MDI aerosolcontainer, in particular a standard MDI aerosol container made ofaluminum or an aluminum alloy as well as MDI aerosol containers made ofother metals, such as stainless steel. Methods described herein can alsobe advantageously used to provide a coating on at least a portion of asurface (preferably the entire surface) of a valve stem or a valve body,in particular a valve stem or a valve body made of a polymer such as PBTor acetal. This is advantageous for large scale manufacturing andcoating as well as stream-lining of manufacturing processing, facilitiesand/or equipment for coating, while at the same time allowing freedom inregard to the selection of the base material of a component and in someinstances expanding the possibilities of the base material for acomponent.

As detailed above, some polyfluoropolyether-containing coatingsdescribed herein are advantageously transparent or translucent (inparticular those coatings have a thickness of 100 nm or less), and suchcoatings can be used to provide a transparent or translucent plastic MDIaerosol container which can be advantageous in that a patient can easilymonitor the content of the container (i.e. whether it is empty and needsto be replaced).

Methods described herein can also be used to provide other medicinalinhalation devices including nebulizers, pump spray devices, nasalpumps, non-pressurized actuators or components of such devices.Accordingly medicinal inhalation devices or components described hereinmay also be nebulizers, pump spray devices, nasal pumps, non-pressurizedactuators or components of such devices.

Methods described herein can also be used to provide other componentsused in medicinal inhalation such as breath-actuating devices,breath-coordinating devices, spacers, dose counters, or individualcomponents of such devices, spacers and counters, respectively.Accordingly components described herein may also be breath-actuatingdevices, breath-coordinating devices, spacers, dose counters, orindividual components of such devices, spacers, counters, respectively.In regard to provision of a component or components of dose counters ofmedicinal inhalation devices, due to desirable surface properties andstructural integrity (in particular durability and resistance to wear)of coatings described herein, the provision of such a coating on acomponent or components (in particular movable component(s) and/orcomponent(s) in contact with a movable component) of a dose counterprovides dry lubricity facilitating smooth operation of the dosecounter.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

Examples Exemplary Silane Treatment Methods

The following are exemplary silane treatment methods:

Method A:

Place a solution (3 liters (L)) of 0.1% (w/w)

C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—C(O)N(H)(CH₂)₃Si(OCH₃)₃ (average value ofp is 10, average MW of silane is about 2151, and fraction of silane witha polyfluoropolyether segment having a weight average MW lower than 750is zero), 0.6% (w/w) tetraethoxysilane and 1% (w/w) acetic acid inHFE-7200 fluid (available from 3M Company, St. Paul, Minn. under thetrade designation “NOVEL HFE-7200”) in a 4-L beaker at room temperature,and place beaker in a dip coater. Fix component to be coated verticallyabove the solution, introduce component into the solution at acontrolled rate of 15 millimeters per second (submerging the componententirely in the solution) and hold in place for at least five seconds.Subsequently withdrawn component from the solution at a controlled rateof 15 millimeters (mm) per second and allow to drain. After draining,place component in an aluminum pan and then place the pan in an oven at120° C. for 30 minutes. After removing from oven, allow component tostand at least 24 hours.

Method B:

The method is the same as Method A with the exception of placing asolution (3 liters (L)) of 0.1% (w/w)C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—C(O)N(H)(CH₂)₃Si(OCH₃)₃ (average value ofp is 10, average MW of silane is about 2151, and fraction of silane witha polyfluoropolyether segment having a weight average MW lower than 750is zero), and 0.6% (w/w) 3-glycidoxypropyltrimethoxysilane and 1% (w/w)acetic acid in HFE-7200 fluid in a 4-L beaker.

Method C:

The method is the same as Method A with the exception of placing asolution (3 liters (L)) of 0.1% (w/w)C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—C(O)N(H)(CH₂)₃Si(OCH₃)₃ (average value ofp is 10, average MW of silane is about 2151, and fraction of silane witha polyfluoropolyether segment having a weight average MW lower than 750is zero), 0.6% (w/w) tetraethoxysilane, 0.2% (w/w)3-glycidoxypropyltrimethoxysilane, and 1% (w/w) acetic acid in HFE-7200fluid in a 4-L beaker.

Thickness of a coating resulting from following any one of Methods A toC is in the range of about 50 to about 80 nanometers.

Examples 1 to 3

Standard deep drawn aluminum MDI containers having a nominal volume of10 milliliters are washed with trichloroethylene and coated inaccordance with Method A (Example 1), Method B (Example 2) and Method C(Example 3), respectively. Containers are fitted with metered dosevalves of the type marketed under the trade designation SPRAYMISER (3MCompany, St. Paul, Minn., USA) having a 50 mcl metering chamber and thena formulation consisting of 1.97 mg/ml albuterol sulfate (having amajority of particles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Examples 4 to 6

Standard deep drawn aluminum MDI containers having a volume of 10millimeters are washed with trichloroethylene, anodized and coated inaccordance with Method A (Example 4), Method B (Example 5) and Method C(Example 6), respectively. Containers are fitted with metered dosevalves of the type marketed under the trade designation SPRAYMISER (3MCompany, St. Paul, Minn., USA) having a 50 mcl metering chamber and thena formulation consisting of 1.97 mg/ml albuterol sulfate (having amajority of particles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Examples 7 to 9

Standard deep drawn aluminum MDI containers having a volume of 10millimeters are washed with trichloroethylene, exposed to a coronadischarge and then are coated in accordance with Method A (Example 7),Method B (Example 8) and Method C (Example 9), respectively. Containersare fitted with metered dose valves of the type marketed under the tradedesignation SPRAYMISER (3M Company, St. Paul, Minn., USA) having a 50mcl metering chamber and then a formulation consisting of 1.97 mg/mlalbuterol sulfate (having a majority of particles in the range of 1 to 3microns) and HFA 134a is pressure-filled into the canisters.

Examples 10 and 12

Aluminum MDI containers having a volume of 10 millimeters are deep drawnusing methyl nonafluorobutylether as a drawing oil and after forming arecoated in accordance with Method A (Example 10), Method B (Example 11)and Method C (Example 12), respectively. Containers are fitted withmetered dose valves of the type marketed under the trade designationSPRAYMISER (3M Company, St. Paul, Minn., USA) having a 50 mcl meteringchamber and then a formulation consisting of 1.97 mg/ml albuterolsulfate (having a majority of particles in the range of 1 to 3 microns)and HFA 134a is pressure-filled into the canisters.

Examples 13 and 15

Compression springs, primary valve bodies and machined valve stems, allof stainless steel, for metered dose valves of the type similar to thatshown in FIG. 1 having a 63 mcl metering chamber are washed withtrichloroethylene and coated in accordance with Method A (Example 13),Method B (Example 14) and Method C (Example 15), respectively, and thenrespective valves are constructed and crimped onto standard aluminum MDIcontainers containing a chilled formulation consisting of 1.97 mg/mlalbuterol sulfate (having a majority of particles in the range of 1 to 3microns) and HFA 134a (within a dehumidified glovebox).

Examples 16 and 18

Standard deep drawn aluminum MDI containers having a nominal volume of12.5 milliliters are washed with trichloroethylene and coated inaccordance with Method A. Compression springs, primary valve bodies andmachined valve stems, all of aluminum, for metered dose valves of thetype similar to that shown in FIG. 1 having a 63 mcl metering chamberare washed with trichloroethylene and coated in accordance with Method A(Example 16), Method B (Example 17) and Method C (Example 18),respectively, and then respective valves are constructed and crimpedonto the containers. A formulation consisting of 1.97 mg/ml albuterolsulfate (having a majority of particles in the range of 1 to 3 microns)and HFA 134a is pressure-filled into the canisters.

Examples 19 to 21

Acetal valve stems for valves of the type marketed under the tradedesignation BK357 (Bespak plc, Bergen Way, Kings Lynn Norfolk PE 30 2JJ)having a 50 mcl metering chamber are coated in accordance with Method A(Example 19), Method B (Example 20) and Method C (Example 21),respectively, and then the respective valves are constructed and crimpedonto standard deep drawn aluminum MDI containers. A formulationconsisting of 1.97 mg/ml albuterol sulfate (having a majority ofparticles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Example 22

PBT primary valve bodies for valves of the type marketed under the tradedesignation BK357 (Bespak plc, Bergen Way, Kings Lynn Norfolk PE 30 2JJ)having a 50 mcl metering chamber are exposed to a corona discharge andcoated in accordance with Method A, and then valves are constructed andcrimped onto standard deep drawn aluminum MDI containers. A formulationconsisting of 1.97 mg/ml albuterol sulfate (having a majority ofparticles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Examples 23 and 24

PBT primary valve bodies for valves of the type marketed under the tradedesignation BK357 (Bespak plc, Bergen Way, Kings Lynn Norfolk PE 30 2JJ)having a 50 mcl metering chamber are coated in accordance with Method B(Example 23) and Method C (Example 24), respectively, and thenrespective valves are constructed and crimped onto standard deep drawnaluminum MDI containers. A formulation consisting of 1.97 mg/mlalbuterol sulfate (having a majority of particles in the range of 1 to 3microns) and HFA 134a is pressure-filled into the canisters.

Examples 25 to 27

Acetal valve stems and PBT primary valve bodies for valves of the typemarketed under the trade designation BK357 (Bespak plc, Bergen Way,Kings Lynn Norfolk PE 30 2JJ) having a 50 mcl metering chamber areexposed to a corona discharge and coated in accordance with Method A(Example 25), Method B (Example 26) and Method C (Example 27),respectively, and then respective valves are constructed and crimpedonto standard deep drawn aluminum MDI containers. A formulationconsisting of 1.97 mg/ml albuterol sulfate (having a majority ofparticles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Examples 28 and 29

Acetal valve stems and PBT primary valve bodies for valves of the typemarketed under the trade designation BK357 (Bespak plc, Bergen Way,Kings Lynn Norfolk PE 30 2JJ) having a 50 mcl metering chamber arecoated in accordance with Method B (Example 28) and Method C (Example29), respectively, and then respective valves are constructed andcrimped onto standard deep drawn aluminum MDI containers. A formulationconsisting of 1.97 mg/ml albuterol sulfate (having a majority ofparticles in the range of 1 to 3 microns) and HFA 134a ispressure-filled into the canisters.

Example 30

Polypropylene actuators of the type similar to that shown in FIG. 1 areexposed to a corona discharge and coated in accordance with Method A.

Examples 31 and 32

Polypropylene actuators of the type similar to that shown in FIG. 1 arecoated in accordance with Method B (Example 31) and Method C (Example32), respectively.

1. A method of making a medicinal inhalation device or a component of amedicinal inhalation device, said method comprising a step of: applyingto at least a portion of a surface of the device or the component,respectively, a composition comprising a monofunctionalpolyfluoropolyether silane and a non-fluorinated cross-linking agent. 2.A method according to claim 1, wherein the polyfluoropolyether segmentof the polyfluoropolyether silane is not linked to the functional silanegroup(s) via a functionality that includes nitrogen-silicon bond or asulfur-silicon bond.
 3. A method according to claim 1, wherein thepolyfluoropolyether segment of the polyfluoropolyether silane is linkedto the functional silane group(s) via a functionality that includes acarbon-silicon bond.
 4. A method according to claim 3, wherein thepolyfluoropolyether segment of the polyfluoropolyether silane is linkedto the functional silane group(s) via a —C(R)₂—Si functionality where Ris independently hydrogen or a C₁₋₄ alkyl group.
 5. A method accordingto claim 4, wherein the polyfluoropolyether segment of thepolyfluoropolyether silane is linked to the functional silane group(s)via a —(CR₂)_(k)—C(R)₂—Si functionality where k is at least 2 and whereR is independently hydrogen or a C₁₋₄ alkyl group.
 6. A method accordingto claim 1, wherein the polyfluoropolyether segment of thepolyfluoropolyether is a perfluorinated polyfluoropolyether segment. 7.A method according to claim 6, wherein in the repeating units of theperfluorinated polyfluoropolyether segment the number of carbon atoms insequence is at most
 6. 8. A method according to claim 1, wherein theweight average molecular weight of the polyfluoropolyether segment isabout 1000 or higher.
 9. A method according to claim 1 or 8, wherein theweight average molecular weight of the polyfluoropolyether segment isabout 6000 or less, in particular about 4000 or less.
 10. A methodaccording to claim 1, wherein the cross-linking agent comprises one ormore non-fluorinated compounds, each compound being independentlyselected from the group consisting of a compound having at least twohydrolysable groups and a compound having at least one reactivefunctional group and at least one hydrolysable group.
 11. A methodaccording to claim 1, wherein the composition is applied to saidsurface, such that polyfluoropolyether-containing coating provided onsaid surface has a thickness of at most about 300 nm.
 12. A methodaccording to claim 1 or 11, wherein the composition is applied to saidsurface, such that polyfluoropolyether-containing coating provided onsaid surface has a thickness of at least about 20 nm.
 13. A medicinalinhalation device or a component of a medicinal inhalation device madeaccording to claim
 1. 14. A medicinal inhalation device or a componentof a medicinal inhalation device comprising apolyfluoropolyether-containing coating bonded to at least a portion of asurface of the device or the component, respectively, saidpolyfluorpolyether-containing coating comprising a plurality ofmonofunctional polyfluoropolyether-silane entities cross-linked throughnon-fluorinated cross-linking entities and saidpolyfluorpolyether-containing coating sharing at least one covalent bondwith said surface.
 15. A device or a component according to claim 13 or14, where said medicinal inhalation device is a metered dose inhaler ora dry powder inhaler.